Sometimes it’s COPD . . .Sometimes it’s not

Jacqueline Chang, MD, FCCPChief, Division of Pulmonary/Critical Care

Scripps ClinicLa Jolla, California

Talk Objectives

“Not everyone who wheezes or coughs has COPD”

1. Give due diligence to COPD: update on this common disease with emphasis on diagnosis2. Discuss other diseases which can mimic COPD:

-chronic obstructive asthma-bronchiectasis

Why COPD remains important

• 4th leading cause of death in US and Europe

• COPD mortality in women has doubled over the last 20 years

• Cost of COPD: $87 per capita (1992 dollars)

• 75% of these costs are for exacerbations

What is COPD and how do we diagnose it?

COPD is a preventable and treatable disease, with some significant extrapulmonary effects, whose pulmonary component is characterized by airflow limitation that is not fully reversible

COPD should be considered in anyone with dyspnea and cough with risk factors for the disease and should be

confirmed with spirometry

Prevalence of COPD in general adult population (age 25-75 ): 7% mild disease, 7% moderate disease

Diagnosing COPD

Less than 50% of patients with COPD by spirometric criteria had the diagnosis

Why is the diagnosis of COPD being missed?

Case example

J.K. is a 68 y/o never smoker with SOB, wheezing with “severe asthma”. She presented for a second opinion because her previous physician felt she was non compliant since she was not responding to the medications: singulair, advair, albuterol, allergy shots

Why is she not responding?

History: She denies associated allergic rhinitis, ezcema or atopy.Upon specific questioning, she reports a lifetime exposure to second hand smoke. Growing up both parents smoked. Her husband of 40 years smokes and continues to do so. PFTs: FEV1/FVC =60%. FEVl = 68%. No BDR.Methacholine challenge: negative

Dx: COPD

The “face” of COPD

Risk factors for COPD

1. Tobacco smoke: cigars, cigarettes, pipe, environmental smoke2. Occupational dusts and chemical (vapors, irritants, and fumes)3. Indoor pollution: biomass fuels4. Outdoor pollution

Risk is related to the total burden of inhaled particles over a lifetime

Non-tobacco related exposures and COPD

Occupational exposure estimated to account for 19% of COPD cases overall and 31% cases in non-smokers (MMWR 2002)

European Community Respiratory Health Study: Dust, fumes, gases, or vapor exposure increases risk of chronic bronchitis 30%

Copenhagen study: OR for chronic bronchitis-Long term dust exposure and organic solvents, OR = 1.5-Occupational smoke inhalation, OR = 1.7

Treatment for COPD

•Behavioral: Smoking cessation and exposure reduction•Pharmacologic: Short acting bronchodilators, long acting bronchodilators, phosphodiesterase-4 (PDE4)inhibitors•Adjunctive: pulmonary rehabilitation

Don’t forget smoking cessation

Lung Health Study

RCT of 6000 patients to smoking cessation intervention vs placebo

Mild-moderate COPD

Only studyReduction in mortalityMeaningful effect on lung function

Only RCT to demonstrate that smoking kills

Most important study for COPDSponsor NHLBI

TORCH Trial: Salmeterol and Fluticasone propionate and Survival in Chronic Obstructive Pulmonary Disease

NEJM 2007. 356: 775-789

Randomized, double-blind trial comparing salmeterol (50 µg) plus fluticasone propionate (500 µg twice daily) combination regimen, salmeterol alone, or fluticasone propionate alone versus placebo for a period of 3 years.

Primary outcome: death from any causeOther outcomes: frequency of exacerbations, health status, and spirometric

values

SFC Combination Therapy versus Placebo

Outcome SFC vs Placebo: hazard ratio P value

Probability of death at 3 yr 0.825 0.052

Mod/severe exacerbation 0.75 <0.001

Exacerbation requiring steroids

0.57 <0.001

Exacerbation requiring hospitalization

0.83 0.03

25% reduction in exacerbation (NNT=4)Improved quality of life Improved lung function: For all time points, FEV1 was highest in SFC

SHINE study: randomized double blind multicenter trial of budesonide/formoterol in moderate-severe COPD

Comparison of budesonide/Formoterol 160/4.5 versus Formoterol versus placebo

Primary outcome: reduction in severe exacerbations and FEV1Other outcomes: QOL, reduction in mild exacerbations

Moderate -severe COPD: FEV1 <=50%Mean FEV1 = 1LAverage smoking history: 44 pack years

ERS 2003. 21: 74-81

SHINE study results

Budesonide/formoterol reduced number of severe exacerbation 24% vs placebo and 23% versus formoterol

Budesonide/formoterol improved FEV1 15% compared with placebo and formoterol

Budesonide/formoterol improved symptom scores

4 year study with tiopropium or placebo in patients with COPD who were permitted to use all other respiratory medications

Primary endpoint: rate of decline in FEV1Other endpoints: QOL, exacerbations, mortality

Tiotropium in Chronic Obstructive Pulmonary Disease (UPLIFT)

NEJM. 2008. 359: 1543-54

“Placebo” group were actually aggressively treated.Almost 70% of both groups on steroids60% of both groups on LABAAlmost 30% of both groups on theophylline

UPLIFT Study Results

UPLIFT Summary

Primary endpoint: No difference in the rates of decline in FEV1 between the two groups

Important secondary outcomes:1. Consistently higher lung function2. Improved quality of life3. Reduced number of exacerbations and delay in time to first exacerbation4. Lower mortality (RR: 0.76-0.99)5. Lower respiratory failure ( RR 0.51-0.89)

Roflumilast in symptomatic COPDLancet 2009;374:685-94

Phosphodiesterase inhibitors provide a novel treatment for certain patients with COPD: reduce airway inflammation

Two placebo controlled multi-center trial: moderately severe patients randomised to 500 micrograms roflumilast versus placebo for 52 weeks

Severe airflow obstruction: FEV1< 50%Bronchitic symptomsH/o exacerbations in prior year: steroids or hospitalization

Roflumilast study results

Primary endpoints: Change in FEV1 during treatment, rate of exacerbations3091 patients randomized between the 2 studies: mean FEV1= 1 L

Change in FEV1: in the roflumilast group FEV1 increased 40-50 ml; in the placebo group, FEV1decreased 9ml (p<0.0001)Exacerbations: roflumilast group experienced 16% fewer moderate or severe exacerbations (p<0.0003)

Roflumilast Side Effects

Higher incidence of study withdrawal in roflumilast group in first 12 weeks: centrally mediated effects (insomnia, nausea, HA) and GI (diarrhea)

Roflumilast group experienced greater weight loss: average approx. 5 lbs, attenuated after 6 months

No difference between roflumilast and placebo for the following:pneumonia and pulmonary infectionscardiac events and arrhythmia

COPD versus Asthma

Reversibility of airflow obstruction

COPD: partially reversible airflow obstructionAsthma: significant, if not total, reversibility of airflow

obstruction

Can we always make that distinction?

Chronic Obstructive AsthmaCopenhagen study (NEJM 1998; 339:1194-1200): 15 year longitudinal study of ventilatory function in 19,698 adults with asthma.

Rate of decline greater for patients with asthma than for those without asthma (38 ml/year versus 22 ml/year)

Extrapolation: a 60 y/o man with asthma could have an FEV1=1.99L compared with a man without asthma who would have an FEV1=3.05L

Confirmed that chronic obstruction could develop in long standing asthma

Epidemiologic studies show that 30% of patients with fixed airflow obstruction have a history of asthma

Chronic Obstructive Asthma

Some international guidelines recommend classifying asthma with fixed obstruction COPD

Does it matter ? Are they essentially the same disease?

Yes . . . No . . .

Case example

55 y/o man diagnosed with adult asthma 20 years ago. He used Advair in the distant past but for the last 5 years has been on no controlling agents. Now he has daily asthma symptoms of SOB and tightness and has stopped exercising as a result.

Social history: Smoked lightly for 3-4 years. However worked 28 years as a firefighter, including 14 years working on wild fires on West Coast

Family history: strong history of asthma (both parents, sister)

What type of obstructive disease does he have?

Case example: 55 y/o man

FVC 4.2 L (79%) 6.2 L (117%) + 49%

FEV1 1.1 L (27%) 2.5 L (61%) +122%

FEV1/FVC 0.26 0.40

Pre- Post- % change

Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Fabbri, et al. Am J Resp Crit Care Med 2003. 167 (3); 418-424

Asthma with fixed obstruction is still asthma and distinct from COPD

46 patients with similar fixed airflow obstruction and bronchial responsiveness: 27 COPD and19

Asthma patients were compared

Clinical features

PFTs

BAL and bronchial bx characteristics

HRCT

Asthma with fixed obstruction is still asthma and distinct from COPD

Asthma patients still have prominent airway eosinophiliaFixed obstruction: different mechanism in asthma ( basement membrane

thickening)

Proof of principle: within a group of patients with fixed airflow obstruction, those with a history of asthma have distinct airway inflammation as compared with those with a history of smoking-induced COPD. This finding suggests that asthmatic airway inflammation does not change with the development of fixed airflow obstruction and thus does not become similar to the airway inflammation characteristic of COPD.

Asthma with fixed obstruction is still asthma and distinct from COPD

Inflammatory markers: consistently higher in asthma patientsPFTs: asthma patient have lower residual volumes (less hyperinflation) and higher DLCO and pO2 in bloodHRCT: asthma patients had lower emphysema scoresClinical features: asthma patients still had better response to bronchodilators and steroids and had a better prognosis

Asthma with fixed obstruction has similarities to COPD but is distinct from COPD

Many of the same bronchodilators are used in advanced asthma and COPD: short acting bronchodilators, inhaled corticosteroids/LABA combinations, tiotropium (a long-acting anticholin- ergic agent approved for the treatment of chronic obstructive pulmonary disease)

NHLBI Asthma Clinical Network study:three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma not well controlled on low-moderate doses if ICS

Three arms: (1)addition of tiotropium bromide to an inhaled glucocorticoid compared with (2) doubling of the dose of the inhaled glucocorticoid or (3) addition of LABA (salmeterol)

Tiotropium bromide step-up therapy for adults with uncontrolled asthma. NEJM 2010; 363 (18) 1715-26

Tiotropium added to ICS improved symptoms and lung function

Tiotropium was as effective as salmeterol for all outcomes including symptom control and was superior in its effects on FEV1

Asthma with fixed obstruction has similarities to COPD but is distinct from COPD

Because ongoing eosinophilic and lymphocytic inflammation is ongoing, inhaled corticosteroids remain essential

Montelukast is helpful in asthma but has no role in COPD

Patients may still have allergic triggers and may benefit from any IGE therapy (Xolair)

Adjunctive therapies such as bronchial thermoplasty may be helpful in asthma but have no role in COPD

LABA and the risk of death in asthma

The Salmeterol Multicenter Asthma Research Trial (SMART trial) Chest 2006:129-:15-26.

Comparison: Salmeterol versus placeboStudy stopped because of interim analysis in 26, 355 patients

Small increase in respiratory related death: 24 vs 1 RR=2.16 (CI 1.05-4.41)Small increase in asthma related deaths: 13 vs 3 RR= 4.37 (CI 1.25-15. 34)Small increase in asthma related death or life threatening experiences: 37 vs 22 RR= 1.7 (CI 1.01-2.89)

Safety of LABA among patients with asthma using inhaled corticosteroids:systemic review and meta-analysis Am J of Resp Crit Care Med. 2008 ; 178: 1009-1016

Rational: Given the increase risk of LABAs as monotherapy in asthma, does the same risk exist in patients using ICS/LABA

Study cohort: 62 studies with > 29,000 patients looking at the effects on mortality and morbidity of LABAs in patients taking ICS

15, 710 patients taking LABAS, >8000 patient-years exposure3 asthma related death, 2 intubationsNo difference in asthma related hospitalizations: OR =0.74 (CI 0.53-1.03)No difference in asthma serious events OR =0.75 (CI 0.54-1.03)

Anti-Immunoglobulin E (omalizumab) therapy in Allergic AsthmaAm J Resp Crit Care Med 2001; 164: S 12-17

Randomized double blind placebo controlled trial:

ICS Placebo or omalizumab+ICS

Placebo or omalizumabICS withdrawal

Placebo or omalizamabICS

Run -inphase Efficacy phase

Safety phase

Primary endpoint: Asthma exacerbations in stable steroid and steroid withdrawal phase

Extension phase

Anti-Immunoglobulin E (omalizumab) therapy in Allergic Asthma

The reduction in asthma exacerbations in the omalizumab group occurred despite the significantly greater reduction of BDP dose from baseline to t h e e n d o f t r e a t m e n t i n t h e omalizumab group compared with the placebo group

Omalizumab group associated with more signicant ICS dose reduction or total ICS dose withdrawal

New therapies: bronchial thermoplasty in severe asthmaAIR2 TRIAL. Am J Resp Crit Care Med 2010; 181:116-124

Rationale: Increases airway smooth muscle (ASM) mass and contractility cause increased bronchospasm and obstruction and contribute to asthma morbidity

Bronchial thermoplasty delivers controlled thermal energy to bronchial wall decreasing ASM mass

Randomized (2:1) double blind sham controlled trial in 225 adult patients with severe asthma

Primary endpoint: change in asthma symptoms (AQLQ)Secondary endpoints: PEF, rescue medication use for 12 months, health care utilization

Broncial thermoplasty in severe asthma

Reduced severe exacerbations and ER visits in thermoplasty group compared with sham group

Mean change in AQLQ score was higher in thermoplasty group complared with the sham group

Bronchial thermoplasty - adverse events

Events during the treatment period: higher in thermoplasty groupAirway irritation/bronchospasm = asthma symptomsUpper respiratory tract infection8.4% thermoplasty group required hospitalization2% sham group required hostpializationMajority of these event occurred within 1 day of the procedure and resolved by 7 days post procedureEvents during post procedure period: fewer in thermoplasty group36% risk reduction of asthma symptoms84% risk reduction of ER visits

Case: a second opinion for shortness of breath, wheezing, and cough

61 y/o retired farmer from Bakersfield , CATreated for the last 5 years for asthma with Advair, singulair, albuterol desensitization therapy. None have helped. Steroid pulse did not help.

Outside workup: allergy testing (allergic to most weeks, trees and grasses, less so to mold and dust mites)

Peak flow self monitoring: varies by 150 and albuterol changes is minimally

One of his biggest complaints: chronic cough

Is his diagnosis asthma?

Asthma versus COPD versus Bronchiectasis ?

COPD risk factors: 1 ppd for 20 years, quite 30 years agoLifetime exposure to dust and organic materials (cotton and wheat)

Exam: O2 sat 97% and lungs were clearPFTs: FEV1 = 75% predicted, DLCO WNL, no BD response

Serum IgE level normalHRCT scan: bronchiectasis

Conclusion: COPD with bronchiectasis

Bronchiectasis in COPD patientsChest 2011. 140 (5): 1130-1137.

Prospective study assessing the prevalence of bronchiectasis in patients with moderate-severe COPD: 106 patients over 2 year period with COPD but w/o any prior dx of bronchiectasis

All patients evaluated with clinical questionnaires, PFTs, sputum samples, and HRCT

Bronchiectasis by HRCT was found in 57% of moderate COPD patients and 73% of severe COPD patients

Bronchiectasis in COPD patients

COPD patients with bronchiectasis:more symptoms of chronic coughmore exacerbationsmore likely to have positive sputums for pathogenic organisms

Bronchiectasis may be an incidental finding with implications for prognosis and therapy

Chest 2011. 140 (5): 1130-1137.

Burden of Bronchiectasis

Some estimates of prevalence:All ages: 25 per 100,000Elderly 75+ years old: 272 per 100,000

Economic burden is great (2001 estimated annual cost to care for a patient)Bronchiectasis $13, 244*COPD $11,000-13,000Heart disease $12,000

*Cost is greater in patients with resistant organisms requiring IV antibiotics

Bronchiectasis: a vicious cycle of damage

Bronchial damage causes chronic enlargement

Decreased ability to clear secretions

Collection of microbes and particles

Further secretions and inflammation

Further damage to airways

Diagnosing bronchiectasis

Clinical index of suspicion:symptoms- chronic cough, sputum, prior unusual pathogens, recurring infectioncompatible personal history- prior infection (childhood illness,pertussis, tuberculosis), pneumoniafamily history- cystic fibrosis, immunodeficiencies

Pulmonary function testing: NOT UNIQUEObstructiveMay show strong bronchodilator response

Imaging:CXR insensitiveHRCT scan is the gold standard

Bronchiectasis on CT scan

Bronchial dilation and thickening: signet ring sign

Bronchiectasis treatments

Similarities to other obstructive lung diseases:Bronchodilators (nebulized treatments over MDIs or powder inhalers)

Differences from other obstructive lung diseases:Antibiotics (early administration, importance of culture directed therapy, screening for atypical organisms)Secretion mobilization or “pulmonary toilet”

- hypertonic saline, mucomist-clearance mechanisms: exercise, acapella valve, fluter device, vibratory vest

Take home points“Not every patient who wheezes has COPD”

Try to define the phenotype based upon clinical features, risk factors, PFTs, and imaging

Asthma-Atopic history-symptoms of bronchoreactivity-PFTS: more likely bronchoreactivity, preserved DLCO-CT: air trapping without emphysema

COPD-risk factors: lifetime burden of inhaled irritants-symptoms of chronic bronchitis-PFTs: Less often strong bronchoreactivity-CT: emphysema

Bronchiectasis-risk factors: prior infections/ pna or immunodeficiency-more prominent cough and frequent infections-atypical organisms-CT scan: bronchial dilation and thickening-Bronchoscopy: airway thinning and pitting